Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Roser Torra

Alport syndrome (AS) is a progressive hereditary renal disease accompanied by sensorineural hearing loss and ocular abnormalities. AS develops because of pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes encoding type IV collagen α3, α4, and α5 chains that constitute the glomerular basement membrane (GBM). It is divided into three modes of inheritance, namely, X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, while ADAS and ARAS are caused by those in COL4A3/COL4A4[1].

The need for a new classification system of AS
The term ADAS has historically been reserved for patients with heterozygous mutations in COL4A3 or COL4A4, but with renal failure. The problem is that a single patient, with a known mutation, can have different diagnoses over a lifetime depending on the clinical presentation; thus, for example, a diagnosis of thin basement membrane disease in young adulthood may be replaced by ADAS if renal failure develops. In addition, within a family, different members may have different diagnoses based on clinical grounds. In comparison with autosomal dominant polycystic kidney disease (ADPKD) it would be like assigning the diagnosis of ‘a few renal cysts’ to a young adult and switching it to ADPKD when the number of cysts increases and the patient develops renal failure. However, this is not merely a semantic issue, for two main reasons. First, the prevalence of heterozygous mutations in COL4A3 and COL4A4 among renal patients is in fact much higher than expected. Secondly, the advent of new treatments for AS should also benefit any patient with abnormal GBM caused by mutations in the COL4A3, COL4A4 and COL4A5 genes who presents with signs of rapid progression, independently of the name of the disease[2].

Pathogenic variants, distribution and phenotypic variability of AS
In a combined cohort of more than 3000 patients with chronic kidney disease (CKD), exome sequencing revealed a genetic diagnosis in about 10% of cases, of which glomerulopathy due to mutations in COL4A3, COL4A4 or COL4A5 was observed in 30% of cases, similarly to ADPKD which was observed in 31% of patients. Compared to the patients with ADPKD, most of the patients with AS did not have previous clinical diagnosis [3].

Having only one mutation in COL4A3 or COL4A4 can cause a phenotype that ranges from nothing to haematuria alone or to proteinuria and subsequent renal failure. Possible explanations for phenotypic variability in AS are summarized in Figure 1[4].

Figure 1. Possible explanations for phenotypic variability in AS [4].


Current therapy for AS
The long-term effect of a drug in a patient with AS is probably greater if that drug is started early, before any renal insufficiency appears. Unfortunately, at present, there is no curative treatment for AS, so all males with X-linked disease and all males and females with ARAS, as well as a certain percentage of patients with ADAS, will ultimately show progression to end-stage renal disease (ESRD). Currently, the only recommended treatment is renin–angiotensin–aldosterone system (RAAS) blockade[2].

RAAS inhibitors have been shown to delay progression to Stage 5 CKD in adult patients with proteinuric nephropathies as they have anti-proteinuric effects beyond their effects on blood pressure[5]. In AS, early therapy with angiotensin-converting enzyme inhibition (ACEI) delays renal failure and improves life expectancy in a time-dependent manner [6]. Similar finding was also noticed in patients with XLAS and ADAS, where timely therapy with RAAS inhibitors delayed the onset of ESRD[7]. Ongoing EARLY PRO-TECT Alport Trial is examining the safety and efficacy of ramipril in paediatric patients with AS. This study will shed the light about efficacy of ramipril in AS children before they develop albuminuria, when they are presenting only with microhaematuria[8].

Novel therapeutic targets in AS
MicroRNAs (miRNAs) are small non-coding RNAs that regulate post-transcriptional gene expression and modulate crucial biological processes, including differentiation, proliferation and apoptosis. The miRNA-21 seems to be particularly involved in AS. It contributes to the pathogenesis of fibrogenic diseases in multiple organs, including the kidneys, and is thought to be involved in regulating tissue repair responses after injury. Engineered oligonucleotide directed against specific miRNA-21 (anti-miRNA-21) was found to prevent progression of Alport nephropathy by stimulating metabolic pathways. The drug, administered subcutaneously, concentrated extensively within proximal tubule epithelium and improved kidney function as well as both glomerular and interstitial histology, with a resultant improvement in renal function biomarkers, including microalbuminuria. Furthermore, the median lifespan of the mice was increased by >40% [2, 9].

Bardoxoloneis an antioxidant inflammation modulator that activates the Keap1–Nrf2 pathway, which is known to play an important role in maintaining kidney function and structure. Bardoxolone was shown to increase estimated GFR (eGFR) in patients with Type 2 diabetes and Stage 3 CKD [10]. This finding encouraged the researchers to perform a randomized clinical trial in diabetic nephropathy, so called the BEACON trial. Unfortunately, the trial was terminated because of a higher rate of heart failure hospitalizations among those assigned to bardoxolone [11]. Driven by the fact that inflammation is a common element in most causes of CKD as it is in AS, the CARDINAL trial is being conducted. Phase 2 of this trial involved 30 patients and showed that bardoxolone increased eGFR in patients with AS after 48 weeks for 10.4 mL/min/1.73 m2. Additionally, a significant increase of eGFR from baseline at week 52 after withdrawal of active drug for 4 weeks by a mean of 4.1 mL/min/1.73 m2 was also noted in patients who received bardoxolone (Figure 2), suggesting that the drug may delay kidney failure, or prevent it altogether. However, there are some concerns regarding this trial. First, the rapid increase in GFR observed in previous studies raises questions over the extent to which the increase is due to fluid overload and excess pressure in glomerular capillaries, which may prompt hyperfiltration and exacerbate the decline in GFR in the long run. Secondly, an increase in proteinuria has been observed in early trials. The explanation provided for both findings is that bardoxolone increases the filtering surface, which increases GFR with a relative increase in proteinuria. This is an important concern in AS, where present therapies aim to lower the amount of proteinuria, with positive outcomes. The reasonable concern that an increase in urine albumin excretion may result in an acceleration in the rate of decline in GFR due to tubular and interstitial damage from excessive albumin filtration will hopefully be answered by the extension of the CARDINAL trial. The Phase 3 portion of this trial is randomized, double blind and placebo controlled, with a duration of 2 years and with 157 patients enrolled. Data are expected in the second half of 2019 [2, 12].

Figure 2. CARDINAL Phase 2 trial, one year results (Slide 27) [13]


Epidermal growth factor receptor (EGFR) inhibition has been proven to be effective in an experimental nephritis models. However, Omachiet al showed that treatment with erlotinib, EGFR inhibitor, suppressed renal inflammatory cytokine expression but did not show significant positive effects on AS renal pathology in X-linked AS mice. This lack of effect may suggest that other signalling pathways besides EGFR are seminal in AS. Moreover, EGFR inhibitors usually have an unacceptable safety profile [2, 14].

The combination of paricalcitol, a ‘selective’ vitamin D receptor activator, and ACEIs may delay progressive renal fibrosis and renal failure due to a synergistic effect. However, to date there is not enough evidence in humans to fully recommend its use in AS patients [2, 15].

Lipotoxicity may contribute to the pathogenesis of glomerular diseases. In AS mice, hydroxypropyl-b-cyclodextrin protects AS mice against the development of proteinuria, progressive renal failure and fibrosis, and improves survival. In adult patients with AS and incident hypercholesterolemia, statins might be an additional treatment option to delay renal failure and prevent cardiovascular events [13].
In AS, around 50% of mutations are missense mutations. In many of these cases an abnormal protein is secreted but does not pass the quality control of the endoplasmic reticulum (ER) which degrades or retains the misfolded chains. This is accomplished through the unfolded protein response (UPR) pathway, which is activated by the ER stress. Chaperones have been proven to be effective in several diseases and there is already a commercial chaperone for an inherited kidney disease: migalastat for Fabry disease. In AS, a chaperone could promote triple-helix formation and consequently allow misfolded collagen IV proteins to reach their destination and function suboptimally but nevertheless sufficiently well to grant a resistant GBM [2]. Treatment of cells expressing mutant laminin β2 (LAMB2) gene with the chemical chaperone taurodeoxycholic acid (TUDCA) can facilitate protein folding and trafficking, and increase the secretion of the mutant LAMB2 protein [16]. A charoperone, sodium 4-phenylbutyrate increases collagen IV α5 mRNA levels, reduces ER stress and autophagy, and possibly facilitates collagen IV α5 extracellular transport [17].

The rationale of stem cell-based therapy in AS is that these cells isolated from healthy donors will migrate and engraft in renal glomeruli, where they may differentiate into functional podocytes, producing a new functional GBM to prolong kidney function. Moschidou et al found that human first trimester foetal chorionic stem cells are able to migrate to glomeruli and to differentiate down the podocyte lineage in vitro and in vivo, with a delay in progression of renal pathology due to a combination of anti-inflammatory effects and replacement of the defective resident podocytes in mice. Bone marrow transplantation (BMT) has been studied in mice models of AS but unfortunately, itis a very aggressive procedure usually performed in life-threatening diseases. The uncertainties in the studies of BMT in mouse models of AS prevent the use of this treatment in AS patient [2, 18].
Other treatment options including CRISP/Cas9 genome editing, empaglifozin, pentraxin-2, STAT3 inhibition, LOXL2 inhibition and DDR1 inhibition also showed promising results in treating AS[13].


1. Nozu K, Nakanishi K, Abe Y, et al. A review of clinical characteristics and genetic backgrounds in Alport syndrome. ClinExpNephrol. 2019;23(2):158–168. doi:10.1007/s10157-018-1629-4

2. Torra R, Furlano M. New therapeutic options for Alport syndrome. Nephrol Dial Transplant. 2019; pii: gfz131. doi: 10.1093/ndt/gfz131.

3. Groopman E, Marasa M, Cameron-Christie S, et al. Diagnostic Utility of Exome Sequencing for Kidney Disease. New England Journal of Medicine. 2019;380(2):142-151.

4. Ars E, Torra R. Rare diseases, rare presentations: recognizing atypical inherited kidney disease phenotypes in the age of genomics. Clin Kidney J. 2017;10(5):586–593. doi:10.1093/ckj/sfx051

5. Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–869

6. Gross O, Licht C, Anders HJ et al. Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int. 2012 Mar;81(5):494-501. doi: 10.1038/ki.2011.407.

7. Temme J, Peters F, Lange K, et al. Incidence of renal failure and nephroprotection byRAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessiveAlport mutations. Kidney Int. 2012;81(8):779-83. doi: 10.1038/ki.2011.452

8. Gross O, Friede T, Hilgers R et al. Safety and efficacy of the ACE-inhibitor ramipril in Alport syndrome: the double-blind, randomized, placebocontrolled, multicenter Phase III EARLY PRO-TECT Alport trial in pediatric patients. ISRN Pediatr 2012; 2012: 1

9. Gomez IG, MacKenna DA, Johnson BG et al. Anti-microRNA-21oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. J Clin Invest. 2015;125(1):141-56. doi: 10.1172/JCI75852.

10. Pergola PE, Raskin P, Toto RD et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med. 2011;365(4):327-36. doi: 10.1056/NEJMoa1105351.

11. de Zeeuw D, Akizawa T, Audhya P et al. Bardoxolone methyl in type 2 diabetes andstage 4 chronic kidney disease. N Engl J Med. 2013;369(26):2492-503. doi: 10.1056/NEJMoa1306033.

12. Identifier: NCT03019185. A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients WithAlport Syndrome – CARDINAL (CARDINAL). 2017 Jan 12. Assessed 2019, Oct 22. Available from

13. Torra R.New therapeutic targets in Alport syndrome. 56th ERA-EDTA Congress; June 16, 2019; Budapest, Hungary available on Congress Virtual Meeting

14. Omachi K, Miyakita R, Fukuda R et al. Long-term treatment with EGFR inhibitor erlotinib attenuates renal inflammatory cytokines but not nephropathy in Alport syndrome mouse model. ClinExpNephrol 2017; 21: 952–960

15. Rubel D, Stock J, Ciner A et al. Antifibrotic, nephroprotective effects of paricalcitol versus calcitriol on topof ACE-inhibitor therapy in the COL4A3 knockout mouse model for progressive renalfibrosis. Nephrol Dial Transplant. 2014;29(5):1012-9.

16. Chen YM, Zhou Y, Go G et al. Laminin b2 gene missense mutation produces endoplasmic reticulum stress in podocytes. J Am SocNephrol 2013; 24: 1223–1233

17. Wang D, Mohammad M, Wang Y et al. The chemical chaperone, PBA, reduces ER stress and autophagy and increases collagen IV alpha5 expression in cultured fibroblasts from men with X-linked Alport syndrome and missense mutations. Kidney Int Rep 2017; 2: 739–748

18. Moschidou D, Corcelli M, Hau K-L et al. Human chorionic stem cells: podocyte differentiation and potential for the treatment of Alport syndrome. Stem Cells Dev. 2016; 25: 395–404

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